A predictable response of an insect population to insedticidal pressure is resistance development. Although the physiological mechanisms responsible for insect resistance to insecticides are fairly well understood, relatively little is known about the genetic changes which bring about resistance. The proposed research will investigate the spectrum of genetic changes which can occur in Drosophila melanogaster to confer resistance to lethal application does of either of two compounds. The compounds chosen are juvenile hormone III, a naturally occurring insect hormone, and methoprene, an insecticide which chemically and biologically mimics juvenile hormone; both are lethal to Drosophila when applied in nanogram levels. Several types of genetic changes resulting in resistance will be examined. Point mutants will be induced with a mutagen and those resistant to toxic levels of either compound will be selected. The responsible loci will be characterized and mapped. In parrallel experiments, two Drosophila populations will be subjected to sublethal doses of either of these compounds in order to select for resistant strains for 30-50 generations. One population will be isogenic susceptible wild-type strain, and the other will be an interstrain cross which will result in hybrid dysgenesis in progeny populations. Loci responsible for resistance will be characterized, mapped, and compared to those derived from the mutagenesis screen. Finally, the mechanism of resistance (changes in penetration, metabolism, or excretion of the toxic compound) will be determined in a representative mutant of each locus by application of radiolabelled juvenile hormone III or methoprene. The results of this work will be important for understanding the types (point, spontaneous, dysgenic), genomic location, and relative frequency of mutations responsible for resistance development.